A Multifaceted Imbalance of T Cells with Regulatory Function Characterizes Type 1 Autoimmune Hepatitis

Silvia Ferri; Maria Serena Longhi; Chiara De Molo; Claudine Lalanne; Paolo Muratori; Alessandro Granito; Munther J. Hussain; Yun Ma; Marco Lenzi; Giorgina Mieli-Vergani; Francesco B. Bianchi; Diego Vergani; Luigi Muratori

doi:10.1002/hep.23792

A Multifaceted Imbalance of T Cells with Regulatory Function Characterizes Type 1 Autoimmune Hepatitis

Silvia Ferri, Maria Serena Longhi, Chiara De Molo, Claudine Lalanne, Paolo Muratori, Alessandro Granito, Munther J. Hussain, Yun Ma, Marco Lenzi, Giorgina Mieli-Vergani, Francesco B. Bianchi, Diego Vergani, Luigi Muratori

Research output: Contribution to journal › Article › peer-review

168 Citations (Scopus)

Abstract

Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gamma delta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) cells are impaired in children with autoimmune hepatitis (AM). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in gamma delta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) production by CD4(+)CD25(-) target cells. Liver forkhead box P3-positive (FOXP3(+)) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4(+)CD25(hi) T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8(+)CD28(-) T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, gamma delta T cells in AIH patients were more numerous versus healthy controls and had an inverted V delta 1/V delta 2 ratio and higher IFN-gamma and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3(+) cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and gamma delta T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010;52:999-1007)

Original language	English
Pages (from-to)	999 - 1007
Number of pages	9
Journal	Hepatology
Volume	52
Issue number	3
DOIs	https://doi.org/10.1002/hep.23792
Publication status	Published - Sept 2010

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10.1002/hep.23792

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@article{8f78a511e51740048fa9ddcc67332888,

title = "A Multifaceted Imbalance of T Cells with Regulatory Function Characterizes Type 1 Autoimmune Hepatitis",

abstract = "Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gamma delta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) cells are impaired in children with autoimmune hepatitis (AM). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in gamma delta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) production by CD4(+)CD25(-) target cells. Liver forkhead box P3-positive (FOXP3(+)) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4(+)CD25(hi) T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8(+)CD28(-) T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, gamma delta T cells in AIH patients were more numerous versus healthy controls and had an inverted V delta 1/V delta 2 ratio and higher IFN-gamma and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3(+) cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and gamma delta T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010;52:999-1007)",

author = "Silvia Ferri and Longhi, {Maria Serena} and {De Molo}, Chiara and Claudine Lalanne and Paolo Muratori and Alessandro Granito and Hussain, {Munther J.} and Yun Ma and Marco Lenzi and Giorgina Mieli-Vergani and Bianchi, {Francesco B.} and Diego Vergani and Luigi Muratori",

year = "2010",

month = sep,

doi = "10.1002/hep.23792",

language = "English",

volume = "52",

pages = "999 -- 1007",

journal = "Hepatology",

issn = "1527-3350",

publisher = "Wolters Kluwer Health",

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T1 - A Multifaceted Imbalance of T Cells with Regulatory Function Characterizes Type 1 Autoimmune Hepatitis

AU - Ferri, Silvia

AU - Longhi, Maria Serena

AU - De Molo, Chiara

AU - Lalanne, Claudine

AU - Muratori, Paolo

AU - Granito, Alessandro

AU - Hussain, Munther J.

AU - Ma, Yun

AU - Lenzi, Marco

AU - Mieli-Vergani, Giorgina

AU - Bianchi, Francesco B.

AU - Vergani, Diego

AU - Muratori, Luigi

PY - 2010/9

Y1 - 2010/9

N2 - Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gamma delta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) cells are impaired in children with autoimmune hepatitis (AM). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in gamma delta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) production by CD4(+)CD25(-) target cells. Liver forkhead box P3-positive (FOXP3(+)) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4(+)CD25(hi) T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8(+)CD28(-) T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, gamma delta T cells in AIH patients were more numerous versus healthy controls and had an inverted V delta 1/V delta 2 ratio and higher IFN-gamma and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3(+) cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and gamma delta T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010;52:999-1007)

AB - Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gamma delta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) cells are impaired in children with autoimmune hepatitis (AM). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in gamma delta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) production by CD4(+)CD25(-) target cells. Liver forkhead box P3-positive (FOXP3(+)) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4(+)CD25(hi) T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8(+)CD28(-) T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, gamma delta T cells in AIH patients were more numerous versus healthy controls and had an inverted V delta 1/V delta 2 ratio and higher IFN-gamma and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3(+) cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and gamma delta T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010;52:999-1007)

U2 - 10.1002/hep.23792

DO - 10.1002/hep.23792

M3 - Article

SN - 1527-3350

VL - 52

SP - 999

EP - 1007

JO - Hepatology

JF - Hepatology

IS - 3

ER -

A Multifaceted Imbalance of T Cells with Regulatory Function Characterizes Type 1 Autoimmune Hepatitis

Abstract

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